Real-world experience with therapies for SARS-CoV-2: Lessons from the Italian COVID-19 studies.

The therapeutic armamentarium that has been made available from the beginning of the emergency phase of the COVID-19 pandemic to date is briefly reviewed, and an overview of the real-world clinical evidence published by the Italian medical and scientific community during the last three years is presented herein. Prior to the introduction of a vaccine for SARS-CoV-2, several treatment options were implemented from the onset given the evidence that a "cytokine storm" was present during infection with SARS-CoV-2. However, with the exception of tocilizumab, baricitinib and perhaps anakinra, most studies with anti-cytokine biological agents in patients with severe COVID-19 did not show any significant clinical improvement or decrease in mortality at day 28. The same is true of several repurposed drugs including ivermectin, lactoferrin, interferon ß-1a, lopinavir/ritonavir alone or combined with hydroxychloroquine, and darunavir/ cobicistat, which did not show any benefits in clinical status or mortality. Treatment with neutralizing monoclonal antibodies (mAbs) for COVID-19 is changing continually with the evolution of new viral variants. In Italy, current indications for treatment of COVID-19 outpatients underline that the use of specific mAbs may vary over time depending on the prevalent SARS-CoV-2 variant and the sensitivity to the different mAbs available. Three antiviral drugs against SARS-CoV-2 were studied extensively and initially available in Italy: remdesivir, molnupiravir, and nirmaltrelvir/ritonavir, but at present the latter is the only oral antiviral for SARS-CoV-2 available in Italy. Several real-world studies for the use of nirmatrelvir/ ritonavir in the Italian population have been published. Among the current unmet needs, a clear and universal definition for long COVID along with treatments and prevention are still lacking as is clarity of the pathogenetic mechanisms responsible for it.